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Proteomics of the Lysosome

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Proteomics of the Lysosome View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Biochimica et Biophysica Acta 1793 (2009) 625–635 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamcr Review Proteomics of the lysosome Torben Lübke a, Peter Lobel b,c, David E. Sleat b,c,⁎ a Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Georg-August Universität Göttingen, 37073 Göttingen, Germany b Center for Advanced Biotechnology and Medicine, Piscataway, NJ 08854, USA c Department of Pharmacology, University of Medicine and Dentistry of New Jersey - Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA article info abstract Article history: Defects in lysosomal function have been associated with numerous monogenic human diseases typically Received 16 May 2008 classified as lysosomal storage diseases. However, there is increasing evidence that lysosomal proteins are Received in revised form 24 September 2008 also involved in more widespread human diseases including cancer and Alzheimer disease. Thus, there is a Accepted 30 September 2008 continuing interest in understanding the cellular functions of the lysosome and an emerging approach to this Available online 15 October 2008 is the identification of its constituent proteins by proteomic analyses. To date, the mammalian lysosome has been shown to contain ∼60 soluble luminal proteins and ∼25 transmembrane proteins. However, recent Keywords: fi fi Lysosomal protein proteomic studies based upon af nity puri cation of soluble components or subcellular fractionation to Proteomic obtain both soluble and membrane components suggest that there may be many more of both classes of Mass spectrometry protein resident within this organelle than previously appreciated. Discovery of such proteins has important Lysosomal storage disease implications for understanding the function and the dynamics of the lysosome but can also lead the way Mannose-6 phosphate receptor towards the discovery of the genetic basis for human diseases of hitherto unknown etiology. Here, we subcellular fractionation describe current approaches to lysosomal proteomics and data interpretation and review the new lysosomal proteins that have recently emerged from such studies. © 2008 Elsevier B.V. All rights reserved. 1. Introduction to the lysosome very limited tissue distribution and perform specialized cellular functions e.g. the granzymes of immune cells [6]. Discovered by Christian de Duve over 50 years ago [1], the In addition to the soluble luminal proteins, many integral and lysosome is a cytoplasmic cellular organelle that has risen to peripheral membrane proteins are associated with the lysosome and prominence because of its critical role in cellular function and tissue have a variety of functions including catalysis, transmembrane homeostasis as well as its involvement in numerous human diseases transport of substrates and digestion products, establishment of pH (reviewed in [2,3]). Present in all nucleated eukaryotic cells, the gradients, vesicular transport and maintenance of lysosomal struc- lysosome is delimited by a single-layer lipid membrane and has an tural integrity [3]. acidic internal pH (∼5) that is maintained by an ATP-dependent Classical biochemical and genetic analyses have resulted in the proton pump. The primary cellular function of the lysosome is the characterization of numerous components of the lysosome. More degradation and recycling of macromolecules obtained by endocy- recently, the application of highly-sensitive proteomic approaches has tosis, autophagy and other cellular trafficking pathways. Several lead to the identification of many new proteins that may function in classes of macromolecules are hydrolyzed including proteins, poly- this compartment and for some, lysosomal localization has now been saccharides, lipids and nucleic acids and this is achieved by the verified. It is these new lysosomal proteins that form the focus of this concerted action of numerous soluble catabolic enzymes within the review. Approaches to the discovery and validation of lysosomal lumen of the lysosome, collectively termed acid hydrolases. Acid candidates have recently been reviewed in depth [5] and for the most hydrolases have evolved to function in the low pH of this organelle part, will be outlined in brief here. and possess a wide variety of enzymatic properties. Over 60 of these enzymes and soluble accessory proteins have been described to date. 2. Lysosomes and human disease A number of studies have investigated the proteome of soluble lysosomal proteins from a variety of mammalian tissues and cell types The lysosomal system is of considerable biomedical importance as ([4]; reviewed in [5]) revealing that, for the most part, these proteins alterations in lysosomes and lysosomal proteins are associated with tend to be fairly ubiquitous. However, some lysosomal proteins have numerous human diseases (Table 1) [3,7]. To date, over 50 monogenic human genetic diseases have been identified that are primarily associated with lysosomal dysfunction and the majority of these are fi fi ⁎ Corresponding author. Tel.: +1 732 235 5028. classi ed as lysosomal storage diseases (LSDs). Here, de ciencies in E-mail address: [email protected] (D.E. Sleat). lysosomal proteins, most commonly soluble luminal ones, result in an 0167-4889/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamcr.2008.09.018 626 T. Lübke et al. / Biochimica et Biophysica Acta 1793 (2009) 625–635 Table 1 Established lysosomal proteins and associated human disorders Protein Disease Protein type Protein function Man6-P ABCA2 Membrane Lipid metabolism? ABCB9/TAP-like transporter Membrane Antigen processing ATPase, V-H+ including ∼13 subunits Kufor–Rakeb syndrome/Parkinson disease 9 Membrane Membrane transporter CD68 Membrane CLC-7 Osteopetrosis Membrane Transporter CLN3 protein Ceroid lipofuscinosis, neuronal 3, juvenile Membrane Unknown Cystinosin Cystinosis Membrane Transporter LALP70 Membrane LAPTM4 Membrane LIMP-1/CD63/LAMP-3 Membrane LIMP-2/LGP85 Membrane Lysosomal transport Lipopolysaccharide-induced TNF factor Membrane LITAF LYAAT-1 Membrane Transporter Lysosome-associated membrane Membrane protein 1 (LAMP1) Lysosome-associated membrane Danon disease Membrane Structural, protein import protein 2 (LAMP2) Major facilitator superfamily domain Ceroid lipofuscinosis, neuronal 7, late infantile, Membrane Transporter (?) containing 8 variant Mucolipin Mucolipidosis IV (sialolipidosis) Membrane Membrane transporter Nicastrin Membrane NPC1 protein Niemann-pick disease, type C1 Membrane Membrane transporter (?) Solute carrier family 17 Sialuria (Salla disease) Membrane Membrane transporter 1-O-acylceramide synthase Soluble Catabolic enzyme + Acid ceramidase Farber disease Soluble Catabolic enzyme + Acid lipase Wolman disease Soluble Catabolic enzyme + Alpha-galactosidase A Fabry disease Soluble Catabolic enzyme + Alpha-L-iduronidase Mucopolysaccharidosis type I (Hurler and Scheie Soluble Catabolic enzyme + syndromes) Alpha-N-acetylgalactosaminidase Schindler disease, type I Soluble Catabolic enzyme + Alpha-N-acetylglucosaminidase Mucopolysaccharidosis type IIIb (Sanfilippo Soluble Catabolic enzyme + syndrome B) Arylsulfatase A Metachromatic leukodystrophy Soluble Catabolic enzyme + Arylsulfatase B Mucopolysaccharidosis type VI Soluble Catabolic enzyme + (Maroteaux-Lamy syndrome) Beta-galactosidase Mucopolysaccharidosis type IVb (Morquio Soluble Catabolic enzyme + syndrome B) Beta-glucuronidase Mucopolysaccharidosis type VII (Sly syndrome) Soluble Catabolic enzyme + Beta-hexosaminidase alpha chain Tay–Sachs disease Soluble Catabolic enzyme + Beta-hexosaminidase beta chain Sandhoff disease Soluble Catabolic enzyme + Beta-mannosidase Mannosidosis, beta A, lysosomal Soluble Catabolic enzyme + Carboxypeptidase, vitellogenic-like Soluble Catabolic enzyme ? + Cathepsin B Soluble Catabolic enzyme + Cathepsin D Ceroid lipofuscinosis, neuronal 10, congenital Soluble Catabolic enzyme + Cathepsin F Soluble Catabolic enzyme + Cathepsin H Soluble Catabolic enzyme + Cathepsin K Pycnodysostosis Soluble Catabolic enzyme + Cathepsin L Soluble Catabolic enzyme + Cathepsin O Soluble Catabolic enzyme + Cathepsin S Soluble Catabolic enzyme + Cathepsin Z Soluble Catabolic enzyme + CLN5 protein Ceroid lipofuscinosis, neuronal 5, late infantile, Soluble Unknown + variant Deoxyribonuclease II Soluble Catabolic enzyme + Dipeptidyl-peptidase I Papillon-Lefevre syndrome Soluble Catabolic enzyme + Galactocerebrosidase Krabbe disease Soluble Catabolic enzyme + Gamma-glutamyl hydrolase Soluble Catabolic enzyme + Glycosylasparaginase Aspartylglucosaminuria Soluble Catabolic enzyme + GM2 activator Tay–Sachs disease, AB variant Soluble Accessory protein + Hyaluronidase Mucopolysaccharidosis type IX (hyaluronidase Soluble Catabolic enzyme + deficiency) Iduronate 2-sulfatase Mucopolysaccharidosis type II (Hunter Soluble Catabolic enzyme + syndrome) Interferon gamma inducible protein 30 Soluble Catabolic enzyme + Legumain Soluble Catabolic enzyme + Lysosomal alpha-glucosidase Glycogen storage disease II (Pompe disease) Soluble Catabolic enzyme + Lysosomal alpha-mannosidase Mannosidosis, alpha b, lysosomal Soluble Catabolic enzyme + Lysosomal protective protein/Cathepsin A Neuraminidase deficiency with beta- Soluble Catabolic enzyme/accessory protein + galactosidase deficiency Myeloperoxidase Myeloperoxidase deficiency Soluble Host defence
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